In Patients with Long-Chain Fatty Acid Oxidation Disorders: Results from an Open-Label, Long-Term Extension Study

Received: 27 January 2020 Revised: 31 August 2020 Accepted: 1 September 2020 DOI: 10.1002/jimd.12313

ORIGINAL ARTICLE

Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study

1University of Pittsburgh, Pittsburgh, Pennsylvania 2Ann & Robert H. Lurie Children's Hospital, Chicago, Illinois 3Boston Children's Hospital, Boston, Massachusetts 4University of Utah, Salt Lake City, Utah 5Vanderbilt University Medical Center, Nashville, Tennessee 6USF Health, Morsani College of Medicine, Tampa, Florida 7Children's National Health System, Washington, District of Columbia 8Great Ormond Street Hospital and Institute of Child Health, NIHR Biomedical Research Center (BRC), UCL, London, UK 9National Hospital for Neurology and Neurosurgery, London, UK 10Ultragenyx Pharmaceutical Inc., Novato, California

Correspondence Jerry Vockley, University of Pittsburgh, Abstract 4401 Penn Avenue, UPMC Children's Long-chain fatty acid oxidation disorders (LC-FAOD) are autosomal recessive Hospital of Pittsburgh, Pittsburgh, PA conditions that impair conversion of long-chain fatty acids into energy, leading 15224. Email: [email protected] to significant clinical symptoms. Triheptanoin is a highly purified, 7-carbon chain triglyceride approved in the United States as a source of calories and Communicating Editor: Manuel Schiff fatty acids for treatment of pediatric and adult patients with molecularly con-

Funding information firmed LC-FAOD. CL202 is an open-label, long-term extension study evaluat- Ultragenyx Pharmaceutical; Ultragenyx ing triheptanoin (Dojolvi) safety and efficacy in patients with LC-FAOD. Pharmaceutical Inc Patients rolled over from the CL201 triheptanoin clinical trial (rollover); were triheptanoin-naïve (naïve); or had participated in investigator-sponsored trials/ expanded access programs (IST/other). Results focus on rollover and naïve groups, as pretreatment data allow comparison. Primary outcomes were annual rate and duration of major clinical events (MCEs; rhabdomyolysis, hypoglycemia, and cardiomyopathy events). Seventy-five patients were enrolled (24 rollover, 20 naïve, 31 IST/other). Mean study duration was 23.0 months for rollover, 15.7 months for naïve, and 34.7 months for IST/other.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

J Inherit Metab Dis. 2021;44:253–263. wileyonlinelibrary.com/journal/jimd 253 254 VOCKLEY ET AL.

In the rollover group, mean annualized MCE rate decreased from 1.76 events/ year pre-triheptanoin to 0.96 events/year with triheptanoin (P = .0319). Median MCE duration was reduced by 66%. In the naïve group, median annualized MCE rate decreased from 2.33 events/year pre-triheptanoin to 0.71 events/year with triheptanoin (P = .1072). Median MCE duration was reduced by 80%. The most common related adverse events (AEs) were diarrhea, abdom- inal pain/discomfort, and vomiting, most mild to moderate. Three patients had serious AEs (diverticulitis, ileus, rhabdomyolysis) possibly related to drug; all resolved. Two patients had AEs leading to death; neither drug related. Tri- heptanoin reduced rate and duration of MCEs. Safety was consistent with previous observations.

KEYWORDS cardiomyopathy, long-chain fatty acid oxidation disorders (LC-FAOD), rhabdomyolysis, triheptanoin (UX007)

1 | INTRODUCTION Synopsis Long-chain fatty acid oxidation disorders (LC-FAOD) are Triheptanoin was associated with a reduc- a group of rare, life-threatening, autosomal recessive dis- tion in rate and duration of major clinical orders caused by defects in the mitochondrial carnitine events in patients with LC-FAOD. shuttle or β-oxidation enzymes involved in the conversion of dietary long-chain fatty acids into energy.1,2 There are six LC-FAOD types; three include inherited deficien- even-carbon medium-chain triglycerides (MCT) to bypass cies of enzymes required for β-oxidation: very-long-chain the defect in long-chain fatty acid metabolizing acyl-coenzyme A (CoA) dehydrogenase, long-chain enzymes.10 Expert dietitians assess each patient's energy 3-hydroxyacyl-CoA dehydrogenase (LCHAD), and and nutrient needs based on age, sex, weight, activity trifunctional protein (TFP) deficiency.3 The remaining level, and clinical manifestations. Calorie intake provided three include proteins required for long-chain fatty acid by protein, carbohydrate, and fat are monitored and transport: carnitine palmitoyltransferase I and II and adjusted as required to meet changing patient needs. carnitine-acyl-carnitine translocase. Although not formally studied in a controlled trial, lim- Symptoms of LC-FAOD are heterogeneous, especially ited improvements can be seen for some patients with impacting organs that require high energy production dietary management.7,11 from fatty acid oxidation (FAO), including skeletal mus- Triheptanoin (Dojolvi) is a highly purified, GMP cle, heart, and liver. As a consequence, patients with LC- grade, synthetic odd-carbon medium-chain triglyceride FAOD experience rhabdomyolysis, hypotonia, muscle that is a unique energy substrate replacement therapy for weakness and pain, exercise intolerance, cardiomyopa- patients with LC-FAOD. Triheptanoin is approved in the thy, arrhythmia, hypoglycemia, steatohepatitis, and hepa- United States as a source of calories and fatty acids for tomegaly.1,2,4 Complications and symptoms often result the treatment of pediatric and adult patients with molec- in hospitalizations, emergency room visits, or emergency ularly confirmed LC-FAOD. Upon ingestion, tri- home interventions. Clinical manifestations can be exac- heptanoin is rapidly broken down into free heptanoate erbated during physiological stress due to increased and metabolized by short- and medium-chain FAO energy needs, and patients with LC-FAOD and their enzymes, bypassing the enzymes deficient in LC-FAOD. caregivers show decreased health-related quality of life.5-7 Heptanoate is then metabolized into acetyl-CoA and Mortality rates have been reported as high as 90% but are propionyl-CoA. Acetyl-CoA can enter the tricarboxylic reduced in patients identified with newborn screening, acid (TCA) cycle for ATP production or is diverted to the suggesting a benefit for early disease management.8,9 liver for ketogenesis. Propionyl-CoA is further metabo- Dietary management is the current standard of care, lized to succinyl-CoA, which resupplies TCA cycle inter- with guidelines recommending avoidance of fasting, a mediates (anaplerosis) that may be secondarily deficient low-fat/high carbohydrate diet, and consumption of in patients with LC-FAOD, ultimately providing energy VOCKLEY ET AL. 255 for gluconeogenesis to increase blood glucose and liver guidelines. If a patient was triheptanoin-naïve or was off glycogen stores.12-15 triheptanoin for ≥1 month, dosing was titrated to reach In the CL201 phase 2 study (NCT01886378) in the target dose range. Patients switching from MCT to tri- patients with LC-FAOD, triheptanoin reduced the inci- heptanoin transitioned at the same dose; triheptanoin dence and frequency of hospital days due to major clini- then was titrated per investigator discretion. cal events (MCEs, ie, rhabdomyolysis, hypoglycemia, and cardiomyopathy) and had a positive impact on exercise tolerance, physical health, and vitality.7,16 Here, we 2.2 | Assessments report interim results from CL202, an open-label, extension study evaluating triheptanoin in patients with LC- Baseline was week 0 for patients in the triheptanoin-naïve FAOD to examine long-term effects of triheptanoin and and IST/other groups. For patients in the CL201 rollover replicate results in a naïve population. group, assessments conducted at the last CL201 visit (week 78) were used for baseline data to avoid duplica- tion. Patients visited the clinic at baseline and every 2 | METHODS 6 months and received follow-up telephone calls between clinic visits. Additionally, all patients received an initial 2.1 | Design and participants safety follow-up telephone call 2 weeks and 3 months after their first dose of triheptanoin in this study and CL202 (NCT02214160) is an ongoing, open-label, phase received additional safety follow up as needed. A safety 2 study assessing the efficacy and safety of triheptanoin follow-up phone call was conducted 30 to 35 days after in patients with LC-FAOD. This study is being conducted last dose of study drug. Patients and/or caregivers in 10 centers, 8 in the United States and 2 in the United completed a daily diet diary for 3 days prior to each post- Kingdom. Three cohorts of patients were enrolled: baseline clinic visit which was reviewed by site staff to (a) 24 patients rolling over from the phase 2 triheptanoin calculate daily caloric intake. Adverse events (AEs), MCEs, study CL201 (CL201 rollover group); (b) 20 patients who concomitant medications, and triheptanoin treatment had failed to improve with current dietary guidelines and compliance were monitored at all visits. The full schedule had never received triheptanoin (triheptanoin-naïve of events is available in the supplemental materials. group); and (c) 31 patients who participated in an The primary endpoint was annualized total MCE rate. investigator-sponsored trial or compassionate use pro- MCEs were defined as hospitalizations, emergency room gram with triheptanoin (IST/other group; NCT01461304, visits, or emergency home interventions with a diagnosis NCT01379625, and NCT01461304) (Figure S1). Eligible of rhabdomyolysis, hypoglycemia, or cardiomyopathy. patients were at least 6 months of age with a confirmed MCEs were identified through reporting by patients or diagnosis of LC-FAOD (additional eligibility criteria are caregivers at clinic visits and telephone calls. MCEs were available in the supplementary materials). confirmed with medical record review and source docu- The 18-month period prior to the first dose of tri- ment verification. Each incidence of rhabdomyolysis, heptanoin (or from birth for patients <18 months of age) hypoglycemia, or cardiomyopathy was counted as an was used to establish an internal control for each patient in individual event. Event severity was not captured. Rhab- the 201 rollover and triheptanoin-naïve groups. For these domyolysis, hypoglycemia, and cardiomyopathy were patients, medical records were retrospectively reviewed to selected because these are life threatening events that are document LC-FAOD history, treatment, and MCEs. Inter- common across types of LC-FAOD. The annualized MCE nal controls were not available for the IST/other group. event rate and duration was defined as follows: Patients will receive triheptanoin treatment for up to 5 years, or until commercially available. Triheptanoin MCE event rate = was administered orally at a target of 25% to 35% of total Total number of MCEs daily caloric intake based on tolerability and metabolic Duration of data collection periodðÞ in days =365:25 energy needs. By design, daily caloric intake with MCT was 10% lower than daily caloric intake with tri- MCE duration = heptanoin. Triheptanoin dosing outside this range was ðÞ permitted if the patient was tolerating a different dose Total duration of MCEs in days ðÞ= : prior to enrollment. The only protocol-specified dietary Duration of data collection period in days 365 25 recommendation was a change in medium fat chain dose (usually MCT) while maintaining an isocaloric diet; all Safety was assessed by the frequency and severity of other macronutrients remained in line with standard AEs, vital signs, concomitant medications, cardiac 256 VOCKLEY ET AL. function with echocardiograms, and standard safety labs. during either pre-triheptanoin (for infants with Rhabdomyolysis was captured as both an MCE and <18 months retrospective data collection) or with tri- AE. Functional disability and cognitive development heptanoin (for patients who discontinued the study early were assessed using the physical and mental health com- prior to completing 18 months). The ratio of the event ponent summary scores of the SF-10 or SF-12v2, rate with triheptanoin over pre-triheptanoin was pro- depending on patient age.17,18 vided, along with the two-sided 95% CI and P-value. All statistical tests were two-sided, at a significance level of .05. SAS software version 9.4 was used to perform 2.3 | Analysis analyses.

Statistical analyses were mostly descriptive. For the analysis of MCEs, comparisons were performed between pre- 3 | RESULTS triheptanoin and with-triheptanoin periods using a paired t-test. When the normality assumption was questionable, All six LC-FAOD were represented among the 75 enrolled median values were presented instead of means, and the patients (Table 1). No differences in LC-FAOD type were Wilcoxon signed-rank test (WSRT) was performed as a seen by age. Medical history for all patients reflected nonparametric alternative to the paired t-test. commonly reported LC-FAOD manifestations including Comparisons of MCE frequency and duration rhabdomyolysis (84.0%), muscle pain (72.0%), hypoglyce- between pre-triheptanoin and with-triheptanoin periods mia (61.3%), exercise intolerance (44.0%), cardiomyopa- were also performed using a negative binomial regression thy (41.3%), muscle weakness (36.0%), and failure to model (NBR) to account for different follow-up times thrive (33.3%). Most patients were diagnosed during

TABLE 1 Baseline characteristics

n (%)

Characteristic CL201 rollover n = 24 Triheptanoin-naïve n = 20 IST/other n = 31 Total n = 75 Age group 0-1 y 0 (0.0) 3 (15.0) 0 (0.0) 3 (4.0) >1-6 y 9 (37.5) 6 (30.0) 4 (12.9) 19 (25.3) >6-18 y 9 (37.5) 7 (35.0) 16 (51.6) 32 (42.7) >18 y 6 (25.0) 4 (20.0) 11 (35.5) 21 (28.0) Male 14 (58.3) 12 (60.0) 13 (41.9) 39 (52.0) Race White 21 (87.5) 16 (80.0) 29 (93.5) 66 (88.0) Asian 1 (4.2) 1 (5.0) 0 (0.0) 2 (2.7) Black or African American 1 (4.2) 2 (10.0) 1 (3.2) 4 (5.3) Other 1 (4.2) 1 (5.0) 1 (3.2) 3 (4.0) LC-FAOD deficiency type VLCAD 9 (37.5) 6 (30.0) 11 (35.5) 26 (34.7) LCHAD 9 (37.5) 6 (30.0) 9 (29.0) 24 (32.0) CPT II 3 (12.5) 2 (10.0) 6 (19.4) 11 (14.7) TFP 3 (12.5) 3 (15.0) 4 (12.9) 10 (13.3) CACT 0 (0.0) 2 (10.0) 1 (3.2) 3 (4.0) CPT I 0 (0.0) 1 (5.0) 0 (0.0) 1 (1.3) Prior treatment with MCT 23 (95.8)a 18 (90.0) N/A —

Abbreviations: CACT, carnitine-acyl-carnitine translocase; CoA, coenzyme A; CPT, carnitine palmitoyltransferase; LC-FAOD, long-chain fatty acid oxidation disorder; LCHAD, long-chain 3-hydroxyacyl-CoA dehydrogenase; MCT, medium-chain triglyceride; TFP, trifunctional protein; VLCAD, very-long-chain acyl-CoA dehydrogenase. aPrior treatment with MCT before enrollment in CL201. VOCKLEY ET AL. 257

FIGURE 1 Legend on next page. 258 VOCKLEY ET AL. infancy or early childhood (median age of diagnosis: rate ratio, Figure 1D). In the CL201 rollover group, mean 0.09 years, range: 0.0-56.7 years). At the time of this total MCE rate decreased from 1.8 events/year pre- interim analysis (cutoff June 1, 2018), mean duration in triheptanoin to 1.0 events/year with triheptanoin (annu- CL202 for each group was as follows: CL201 rollover alized event rate ratio: 0.54, 95% CI: 0.33, 0.90, 23.1 months (excludes CL201), triheptanoin-naïve P = .0179). In the triheptanoin-naïve group, mean MCE 15.7 months, and IST/other 34.8 months. Results for the rate decreased from 2.3 events/year pre-triheptanoin CL201 rollover group compare the 18-month pre- period to 1.5 events/year with triheptanoin (NBR; annu- triheptanoin period to the 36-month with-triheptanoin alized rate ratio: 0.66, 95% CI: 0.32, 1.37, P = .2622). period (18 months from CL201 and 18 months from Although all specific event types decreased with tri- CL202). Results for the triheptanoin-naïve group com- heptanoin, only the reduction in hypoglycemia annual- pare the 18-month pre-triheptanoin period to the ized event rate in the CL201 rollover group was 18-month with-triheptanoin period. significantly decreased (rate ratio 0.04; P < .0001).

3.1 | Annualized MCE rates 3.2 | Annualized MCE duration

In the CL201 rollover group, mean (SD) annualized total In the CL201 rollover group, median annualized total MCE rate decreased 45%, from 1.76 (1.64) events/year MCE duration was reduced by 66%, from 5.33 days/year pre-triheptanoin to 0.96 (10.9) events/year with tri- pre-triheptanoin to 1.83 days/year with triheptanoin heptanoin (Figure 1A; P = .0319 paired t-test; median: (P = .3002 WSRT; Figure 1C). By NBR, change in mean from 1.53 to 0.50). For MCE event type, mean annualized annualized total MCE event days was not significant event rate decreased 32% for rhabdomyolysis (mean (6.4 days/year pre-triheptanoin and 5.8 days/year with [SD] events/year: 1.30 [1.53] pre-triheptanoin to 0.89 triheptanoin; P = .8205). Median annualized duration for [1.05] with triheptanoin), 96% for hypoglycemia (0.383 rhabdomyolysis was reduced by 45.0%, from 3.33 days/ [0.98] to 0.014 [0.07]), and 33% for cardiomyopathy year pre-triheptanoin to 1.83 days/year with triheptanoin (0.083 [0.30] to 0.056 [0.21]). More specifically for hypo- (P = .7086 WSRT). By NBR, mean values were 4.0 days/ glycemia, 12 events occurred in four patients during the year pre-triheptanoin and 5.1 days/year with tri- pre-triheptanoin period and only one event occurred dur- heptanoin (P = .5753). Event duration for cardiomyopa- ing the with-triheptanoin period on the patient's first day thy and hypoglycemia were too small pre-triheptanoin of triheptanoin treatment in CL201.16 No hypoglycemia and with triheptanoin for a sufficient comparison. events occurred in the CL201 rollover group during In the triheptanoin-naïve group, median annualized CL202. No marked differences were seen within age total MCE duration was reduced by 80%, from groups Supplemental Table S1). 10.0 days/year pre-triheptanoin to 2.0 days/year with In the triheptanoin-naïve group, median annualized triheptanoin (Figure 1C; P = .1475; WSRT). By NBR, total MCE rate decreased 70%, from 2.33 events/year pre- mean annualized total MCE duration was 17.1 days/ triheptanoin to 0.71 events/year with triheptanoin year pre-triheptanoin and 16.2 days/year with tri- (Figure 1B; P = .1072 WSRT; mean [SD]: from 2.95 [3.010] heptanoin (P = .9230). For MCE event type, median to 7.72 [27.05]). For MCE event type, median annualized annualized rhabdomyolysis duration was reduced event rate for rhabdomyolysis decreased 65%, from 2.00 by 71.4%, from 7.00 days/year pre-triheptanoin to events/year pre-triheptanoin to 0.71 events/year with tri- 2.00 days/year with triheptanoin (P = .3335 WSRT). By heptanoin (P = .2734 WSRT). Median annualized event rate NBR, mean values were 10.7 days/year pre-triheptanoin for hypoglycemia and cardiomyopathy events were 0 during and 15.7 days/year with triheptanoin (P = .4206). Event the pre-triheptanoin and with-triheptanoin periods. duration for cardiomyopathy and hypoglycemia were Rates for annualized total MCE events and specific too small pre-triheptanoin and with triheptanoin for a event types were similar using NBR (NBR; annualized sufficient comparison.

FIGURE 1 Reduction in major clinical events (MCEs) with triheptanoin. Significant P-values provided on the graph. Event rate (triheptanoin-naïve) and duration (both groups) for hypoglycemia and cardiomyopathy were <1 events/year and days/year for both the pre- triheptanoin and with-triheptanoin periods, and, therefore, were not graphed. In the CL201 rollover group, the with-triheptanoin period is comprised of the first 36 months following triheptanoin initiation in studies CL201 and CL202, or from triheptanoin initiation to discontinuation for patients who discontinued. In the triheptanoin-naïve group, the with-triheptanoin period is the first 18 months following triheptanoin initiation during CL202, or from triheptanoin initiation to discontinuation for patients who discontinued VOCKLEY ET AL. 259

3.3 | Annualized hospitalization rates 3.4 | IST/other

In the CL201 rollover group, annualized hospitalization Results for the IST/other group are summarized descrip- event rates significantly decreased by 46.9%, from a mean tively, and no comparisons were done. Mean (SD) rate of 1.43 (1.32) events/year pre-triheptanoin to (SD) annualized MCE rate with triheptanoin was 1.92 0.76 (1.01) events/year with triheptanoin (P = .0429 paired (3.413) (median [Q1, Q3]: 0.67 [0, 2.14]). Mean t-test). Median annualized hospitalization duration was (SD) annualized MCE duration with triheptanoin was reduced by 62.1%, from 4.83 days/year pre-triheptanoin to 9.13 (18.50) (median [Q1, Q3]: 3.18 [0, 7.48]). 1.83 days/year with triheptanoin (P = .4390 WSRT). In the triheptanoin-naïve group, median annualized hospitalization event rate decreased by 83.5%, from 2.00 3.5 | Physical functioning and mental events/year pre-triheptanoin to 0.33 events/year with tri- health heptanoin (P = .2764 WSRT). Median annualized hospitalization duration was reduced by 86.2%, from Both the CL201 rollover and triheptanoin-naïve groups 9.66 days/year pre-triheptanoin to 1.33 days/year with showed normative scores below the healthy reference triheptanoin (P = .2918 WSRT). range (40-60) on the SF-10 and SF-12v2 Physical Health

FIGURE 2 Improvement in physical functioning with triheptanoin. Shaded gray area indicates normal range (40-60) 260 VOCKLEY ET AL.

Summary (Figure 2). The CL201 rollover group Fifty-seven (76%) patients experienced a serious maintained improvements in the Physical Health Sum- AE. Most were hospitalizations for rhabdomyolysis mary score observed in the CL201 study, and the (56.0%, a complication of the underlying disease) or acute triheptanoin-naïve group replicated improvements infectious disease (46.7%). Three patients had serious AEs observed in the CL201 study. Psychosocial Summary considered at least possibly related to triheptanoin by the Scores are available in the supplemental appendix. investigator: diverticulitis (severe), ileus (moderate), and rhabdomyolysis (severe); all resolved. One patient discontinued treatment due to a mild AE of rhabdomyolysis 3.6 | Safety reporting across all groups experienced on the first day of treatment with triheptanoin. For patients in the CL201 rollover group, safety data are There were no noteworthy changes in vital signs, reported for CL202 only. Safety data from CL201 are echocardiograms, or routine hematology, chemistry, uri- summarized in Vockley et al.16 Across all groups, a nalysis laboratory values throughout the trial. majority of patients experienced ≥1 AE, with most AEs grade 1 (mild), 2 (moderate), or 3 (severe) in severity (Table 2). Approximately 49% of patients experienced a 4 | DISCUSSION severe AE of rhabdomyolysis, all but one of these AEs was considered unrelated to triheptanoin (described This study demonstrated that treatment with tri- below). The most commonly reported AEs were charac- heptanoin was associated with reductions in MCE rate teristic of the underlying disease: rhabdomyolysis (61% of and duration and with improvements in physical health. patients overall), upper respiratory tract infection (URI; For patients in the CL201 rollover group, continued treat- 51%), viral URI (37%), vomiting (35%), and diarrhea ment with triheptanoin resulted in sustained improve- (31%). Thirty-four (47%) patients experienced AEs consid- ments.7,16 For patients in the triheptanoin-naïve group, ered at least possibly related to triheptanoin by the inves- improvements were consistent with outcomes in CL201. tigator; most were gastrointestinal events. Nine patients Improvements in physical functioning combined with had a protocol-specified dose reduction (ranging from a fewer MCEs and fewer hospitalizations likely contributed change of 1%-8% daily caloric intake) to manage gastroin- to improved quality of life. testinal symptoms. The safety profile of triheptanoin in this study was There were two deaths, considered unrelated to treat- consistent with the safety profile observed in CL201, with ment, in patients with the TFP type of LC-FAOD, wors- similar rates of rhabdomyolysis and infections.7,16 No ening cardiomyopathy in a 4-year-old patient in the IST/ new safety findings were observed. There were two other group who had been on triheptanoin for 2 years deaths in this study, unrelated to triheptanoin, due to and fatal cardiorespiratory arrest in a 9 month-old patient progressive cardiac symptoms in patients with TFP type in the triheptanoin-naïve group who had been on tri- of LC-FAOD. Although advances in newborn screening heptanoin for 3 months (additional details in supplemen- have improved mortality rates, TFP is a more severe type tal appendix). of LC-FAOD, with patients dying within the first few

TABLE 2 Safety summary for CL202

CL201 Triheptanoin- IST/ Total Category, n (%) rollover (N = 24) naïve (N = 20) other (N = 31) (N = 75) AEs 24 (100.0) 19 (95.0) 31 (100.0) 74 (98.7) Treatment-related AEs 8 (33.3) 14 (70.0) 13 (41.9) 35 (46.7) GI-related AEs 6 (25.0) 12 (60.0) 12 (38.7) 31 (41.3) Grade 3/4 AE 14 (58.3) 12 (60.0) 23 (74.2) 49 (65.3) Serious AEs 18 (75.0) 15 (75.0) 24 (77.4) 57 (76.0) Related serious AEs 1 (4.2) 1 (5.0) 1 (3.2) 3 (4.0) AEs leading to treatment 0 (0.0) 1 (5.0) 0 (0.0) 1 (1.3) discontinuation AEs leading to study discontinuation 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Deaths 0 (0.0) 1 (5.0) 1 (3.2) 2 (2.7)

Abbreviations: AEs, adverse events; GI, gastrointestinal. VOCKLEY ET AL. 261 weeks of life.19 Although there was some improvement Several limitations may be present. Due to the rare in cardiac function following the initiation of tri- nature of these diseases, a placebo control arm on stan- heptanoin in a patient who died from cardiac symptoms, dard dietary treatment with MCT was not included. the heart relies on long chain fats for 60% to 70% of the Instead, historical pretreatment data served as reference required energy supply,20 making depletions in energy for improvement. The sustained benefit observed in the difficult to overcome. CL201 rollover group and replication of results in the The results of this clinical trial are consistent with triheptanoin-naïve group support the clinically mean- findings from previous triheptanoin studies.7,16,21,22 ingful benefits of triheptanoin in patients with LC- Results from the previous triheptanoin study CL201 FAOD. Broad inclusion criteria were employed to ensure showed a 48.1% reduction in mean annualized total MCE access for patients in need with this rare disease. event rate and a 50.3% reduction in mean annualized Although the number of patients within each group was total MCE event duration (days/year) compared to an small, the combined findings are consistent, supporting 18-month pre-triheptanoin period. In this extension a sustained clinical benefit of triheptanoin. NBR study, reductions were sustained in the CL201 rollover accounts for variation in follow-up time (attrition bias) group (45.5% mean reduction in event rate and 65.7% and an ad hoc analysis of the pre-triheptanoin data rev- median reduction in total MCE duration) over an addi- ealed no correlation between MCEs and age, eliminating tional 18 months (36 months total) with triheptanoin. maturation bias. It is unlikely that maturation resulted The triheptanoin-naïve group also showed a consistent in such a dramatic reduction in MCEs with triheptanoin reduction in annualized total MCE event rate (69.5% in all events across all ages and reproduced across inde- median reduction) and duration (80% median reduction). pendent populations within the study. MCEs were iden- Decreases in hospitalizations and cardiomyopathy events tified at the discretion of the physician and verified with observed in this study were also consistent with previous medical review and source document verification; how- observational studies in patients with LC-FAOD receiv- ever, MCE severity was not captured. Across MCEs, few ing triheptanoin through a compassionate use pro- or no intensive care admissions were seen. Thus, robust gram.21,22 Interpretation of changes in cardiomyopathy is analysis of the impact of triheptanoin on MCE severity limited due to the small number of events experienced in and related outcomes such as intensive care admissions the pre-triheptanoin period. While this extension study is not possible. was not specifically designed to detect significant changes Finally, all assessments were identified, recorded, and in clinical events in triheptanoin-naïve patients, the trend analyzed in the same manner pre-triheptanoin and with for both total and specific clinical events mirrored those triheptanoin to mitigate assessment/detection bias. The in other studies, adding to the growing evidence of use of objective endpoints, such as hospitalization, also improvement with triheptanoin for patients with LC- reduces the risk for bias, and if anything, MCEs would be FAOD. Similarly, the continued trend of improved more frequently reported during the triheptanoin treat- clinical course in patients transitioning from the previous ment as a result of cautious monitoring during an inter- triheptanoin study suggests that the effect of triheptanoin ventional study.23 is long lasting. In conclusion, triheptanoin is an odd-carbon, Triheptanoin treatment resulted in a near elimination medium-chain triglyceride designed to replace the energy of hypoglycemia events in this trial and previous tri- deficit and restore oxidative metabolism via the TCA heptanoin studies.16,21 Reduction in hypoglycemia events cycle in patients with LC-FAOD. The results of this study likely reflects the unique attribute of triheptanoin as an and the previous phase 2 study demonstrate that tri- anaplerotic odd-carbon medium chain fat energy replace- heptanoin treatment is associated with reduced MCEs, ment. With triheptanoin, both acetyl-CoA and propionyl- such as rhabdomyolysis, cardiomyopathy, and hypoglyce- CoA are supplied to the TCA cycle through anaplerosis mia, as well as events leading to hospitalizations in to increase energy production, and the increase in energy patients with LC-FAOD compared to pre-triheptanoin production allows production of glucose and repletion of standard of care. Triheptanoin demonstrated an accept- glycogen stores through gluconeogenesis. Enhanced glu- able safety profile, with the most common AEs being coneogenesis sustains blood glucose levels during periods mild to moderate, transient gastrointestinal symptoms. of metabolic stress such as illness in patients with LC- FAOD. This mechanism of action also accounts for the ACKNOWLEDGMENT reduction in rhabdomyolysis and cardiomyopathy, as Funding for this study was provided by Ultragenyx Phar- heart and muscle rely heavily on long chain fats for maceutical Inc. The content of the article has not been energy.20 influenced by the sponsors. 262 VOCKLEY ET AL.

CONFLICT OF INTEREST very-long-chain acyl-CoA dehydrogenase deficiency. J Hum J. C. and X. L. are an employee and shareholder of Genet. 2019;64(2):73-85. Ultragenyx Pharmaceutical Inc. J. V., B. B., G. B., N. L., 5. Siddiq S, Wilson BJ, Graham ID, et al. Experiences of caregivers of children with inherited metabolic diseases: a qualita- J. P., A. S.-V., K. C., P. T., S. G., and E. M. have served as tive study. Orphanet J Rare Dis. 2016;11(1):168. a clinical investigator in clinical trials with the product 6. Evans S, Shelton F, Holden C, Daly A, Hopkins V, manufactured by Ultragenyx Pharmaceutical Inc. MacDonald A. Monitoring of home safety issues in children on enteral feeds with inherited metabolic disorders. Arch Dis AUTHOR CONTRIBUTIONS Child. 2010;95(9):668-672. Jerry Vockley, Jason Cataldo, and Barbara Burton 7. Vockley J, Burton B, Berry GT, et al. UX007 for the treatment participated in study design. Jerry Vockley, Barbara of long chain-fatty acid oxidation disorders: safety and efficacy Mol Burton, Gerard Berry, Nicola Longo, John Phillips, in children and adults following 24weeks of treatment. Genet Metab. 2017;120:370-377. Amarilis Sanchez-Valle, Kimberly Chapman, 8. Baruteau J, Sachs P, Broue P, et al. Clinical and biological fea- Pranoot Tanpaiboon, Stephanie Grunewald, and tures at diagnosis in mitochondrial fatty acid beta-oxidation Elain Murphy participated in data acquisition. defects: a French pediatric study of 187 patients. J Inherit Xiaoxiao Lu participated in data analyses. All authors Metab Dis. 2013;36(5):795-803. participated in data interpretation and drafting of the 9. Wilcken B. Fatty acid oxidation disorders: outcome and long- manuscript. term prognosis. J Inherit Metab Dis. 2010;33(5):501-506. 10. Spiekerkoetter U, Lindner M, Santer R, et al. Treatment INFORMED CONSENT recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis. 2009;32(4): All procedures followed were in accordance with the eth- 498-505. ical standards of the responsible committee on human 11. Roe CR, Brunengraber H. Anaplerotic treatment of long-chain experimentation (institutional and national) and with the fat oxidation disorders with triheptanoin: review of 15years Helsinki Declaration of 1975, as revised in 2000. Institu- experience. Mol Genet Metab. 2015;116(4):260-268. tional review boards/ethics committees approved the pro- 12. Gu L, Zhang GF, Kombu RS, et al. Parenteral and enteral tocol. Informed consent was obtained from all patients metabolism of anaplerotic triheptanoin in normal rats. included in this study. Parents or guardians provided II. Effects on lipolysis, glucose production, and liver acyl-CoA profile. Am J Physiol Endocrinol Metab. 2010;298(2):E362- written informed permission for children to participate, E371. and when appropriate, the subjects' assents were 13. Marin-Valencia I, Good LB, Ma Q, Malloy CR, Pascual JM. obtained before participating. Adult participants provided Heptanoate as a neural fuel: energetic and neurotransmitter their own consent. An external data monitoring commit- precursors in normal and glucose transporter I-deficient (G1D) tee monitored patients' safety and efficacy during the brain. J Cereb Blood Flow Metab. 2013;33(2):175-182. study. The trial is registered with ClinicalTrials.gov 14. Karall D, Brunner-Krainz M, Kogelnig K, et al. Clinical out- (NCT02214160). Documentation of approval from the come, biochemical and therapeutic follow-up in 14 Austrian Institutional Committee for Care and Use of Laboratory patients with long-chain 3-Hydroxy acyl CoA dehydrogenase deficiency (LCHADD). Orphanet J Rare Dis. 2015;10:21. Animals (or comparable committee): Institutional review 15. Karall D, Mair G, Albrecht U, et al. Sports in LCHAD defi- boards/ethics committees, operating in accordance with ciency: maximal incremental and endurance exercise tests in a Title 21 Code of Federal Regulations Part 56, approved 13-year-old patient with long-chain 3-Hydroxy acyl-CoA dehy- the protocol for study UX007-CL202 (NCT02214160). drogenase deficiency (LCHADD) and heptanoate treatment. JIMD Rep. 2014;17:7-12. ORCID 16. Vockley J, Burton B, Berry GT, et al. Results from a 78-week, Jerry Vockley https://orcid.org/0000-0002-8180-6457 single-arm, open-label phase 2 study to evaluate UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders (LC-FAOD). J Inherit Metab Dis. 2018;42: REFERENCES 169-177. 1. Knottnerus SJG, Bleeker JC, Wust RCI, et al. Disorders of mito- 17. 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